Composition containing an acid-labile benzimidazole and process for its preparation

ABSTRACT

The present invention relates to a composition, particularly adapted to oral administration, substantially free of alkaline-reacting compounds. The composition comprises (a) a core containing an acid-labile benzimidazole active principle, where the core comprises a plurality of nuclei and the active principle mixed together and then compressed together, and where the active principle is not in the form of an alkaline salt; (b) an intermediate layer; and (c) an enteric layer; provided that omeprazole is not the benzimidazole active principle. A process for preparing the composition is also disclosed.

This application is a 371 of PCT/IB96/01054 filed Sep. 23, 1996.

BACKGROUND OF THE INVENTION

This present invention relates to a novel composition containing anacid-labile benzimidazole, and to its preparation. This novelcomposition is perfectly suitable for oral administration. The inventionalso relates to a process for preparing this composition.

Many substances, of pharmaceutical value, that are labile in an acidmedium have been described in the literature. The substances disclosedin the following patents can be given by way of example: EP 244 380,U.S. Pat. No. 4,045,563, EP-0 005 129, BE-898 880, GB-2 141 429, EP-0146 370, GB-2 082 580, EP-A-0 173 664, EP-A-0 080 602, EP-0127 763, EP-0134 400, EP-0 130 729, EP-0 150 586, DE-34 15971, GB-2 082 580,SE-A-8504048-3 and U.S. Pat. No. 4,182,766. On the other hand,omeprazole, which is of the family of benzimidazoles, corresponding toan anti-ulcer substance, used conventionally for decreasinggastrointestinal acid secretion, is well known and has been notablydiscussed in Swedish patent application 78.04231 filed on April 14,1978, as well as in numerous other patents. Pantoprazole andlansoprazole which both correspond to anti-ulcer substances of theomeprazole family, are notably discussed in U.S. Pat. No. 4,758,579 andin U.S. Pat. No. 4,628,098 respectively.

Chemical substances that are easily destroyed in an acid medium (whichis expressed herein by the term "acid-labile, and meaning chemicalsubstances that are labile in an acid medium), such as benzimidazolesand, in particular, omeprazole, lansoprazole and pantoprazole, create aspecial problem for formulators when it is required to provide apharmaceutical form designed for oral administration. The product doesindeed come into contact with the stomach content, which is a highlyacid medium, leading to breakdown of these chemical substances.

In order to avoid contact between the substances and the acid gastricjuice following oral administration of the substance, a pharmaceuticalformulation is conventionally used, such as a capsule or tablet whichcontains a core (tablet, microgranule, pellet, etc . . . ) containingthe acid-labile active substance and an outer layer that surrounds thiscore and which consists of a gastro-resistant composition that isentero-soluble. Generally, the coating agent is a compound that isparticularly insoluble in an acid medium, but which is soluble in aneutral or alkaline medium.

For substances that are highly labile in an acid medium but which aremore stable in a neutral or alkaline medium, such as omeprazole,pantoprazole and lansoprazole, it is necessary to add an inert substanceto the composition, which leads to an alkaline reaction aimed atimproving stability of the active substance during manufacture thereof,and during storage of the pharmaceutical form.

Several prior art documents describe such compositions that are suitablefor oral administration of acid-labile substances.

EP-0,244,380 discloses pharmaceutical formulations that are suitable fororal administration of acid-labile substances. It is stated that theseacid-labile substances intended for oral administration must beprotected by an enteric coating, but conventional enteric coatings of anacid nature are not suitable for this purpose. If one were indeed tocover acid-labile substances which such coatings, the substance would berapidly decomposed due to direct or indirect contact with the coating,which manifests itself by a change of color and a decrease in the activesubstance content with the passage of time. The solution proposed inthat patent corresponds to formulations consisting of: (a) a core in theform of small particles, i.e. pellets or compressed powder, containingthe active substance along with an alkaline reacting compound, (b) oneor several inert intermediate layers containing excipients for tabletswhich are soluble, and which rapidly disintegrate in water,water-soluble film-forming polymer compounds optionally containingalkaline compounds acting as a pH buffer between the core having analkaline reaction and the outer layer, and (c) an outer layer consistingof an enteric composition. It is also stated that, in order to improvestorage stability, the cores containing the active substance should alsocontain constituents having an alkaline reaction, and that the waterthat enters by diffusion, or the gastric juice, will dissolve part ofthe core close to the enteric coating, forming an alkaline solution atthis level inside the coated form for administration. This patent claimspharmaceutical formulations containing acid-labile active substances offormula I with the notable exception of omeprazole.

EP-A-0,247,983 which is related to pharmaceutical formulations that aresuitable for oral administration of acid-labile substances adopts thegeneral principles developed in EP-A-0,244,380 in order to moreparticularly apply them to the case of omeprazole. The main claim inthat application thus covers the association of omeprazole with anauxiliary alkaline-reacting substance.

U.S. Pat. No. 4,786,505 discloses novel stable preparations containingomeprazole intended for oral administration, their preparation and amethod for treating gastrointestinal sicknesses using these novelpreparations.

These oral pharmaceutical preparations comprise: (a) a core comprisingomeprazole and an alkaline reacting compound, an alkaline salt ofomeprazole and an alkaline-reacting compound or an alkaline salt ofomeprazole alone; (b) at least one inert intermediate layer that iswater-soluble or rapidly disintegrates in water; and (c) an externallayer comprising an enteric coating.

EP-A-0,519,365 discloses pharmaceutical formulations that are suitablefor oral administration of pantoprazole, comprising an acid-labilesubstance. In order to improve stability of pantoprazole formulations,this document discloses the use of the active substance in a salt form.The pharmaceutical formulations disclosed comprise: (a) a corecontaining the active principle in a salt form, (b) at least onewater-soluble intermediate layer and (c) an outer layer corresponding toan enteric coating. It is stated that the use of a salt form in the coreenables an alkaline environment to be created that protects the activesubstance. If the salt form does not have a sufficient effect on the pH,it is necessary to add a constituent that has an alkaline reaction tothe core.

EP-A-0,519,144 discloses a novel process for producing a stablepreparation containing omeprazole, intended for oral administration.This document notably discloses a process for preparing pelletscontaining omeprazole in which a core constituted of inert substances iscovered by the active substance in finely divided form and dispersed inan aqueous dispersion buffered to a pH of 7.0, after which an entericcoating is applied, the finished product being placed inside a capsule.

U.S. Pat. No. 5,232,706 discloses novel stable pharmaceuticalpreparations containing omeprazole, intended for oral administration.The pharmaceutical compositions disclosed comprised: (a) a corecontaining omeprazole and an alkaline salt of omeprazole mixed with afirst alkaline-reacting compound; (b) at least one intermediate layerformed by an excipient and a second alkaline-reacting compound and (c)an outer layer formed by an enteric coating. It is stated that theproblem of the poor stability of the omeprazole is resolved, firstly, byincreasing the way the core behaves as a base either by introducingomeprazole in the form of an alkali metal or alkaline-earth salt, or amixture of omeprazole with a basic compound or by a combination of thesetwo possibilities; and secondly "by incorporating an intermediate layerbetween the core and the enteric coating for preventing the alkalinecore from causing breakdown of the enteric coating".

FR-A-2,692,146 discloses stable compositions of microgranules ofgastro-protected omeprazole as well as their preparation. This documentsparticularly discloses a stable microgranule formulation of omeprazolecomprising a neutral core consisting of sugar and starch covered with anactive layer constituted by omeprazole diluted in mannitol insubstantially equal amounts, and an intermediate layer comprisingmannitol;an outer layer formed from an enteric coating being optionallypresent. There, it is indicated that the omeprazole is employed in adiluted powder form in an amount that is substantially equal to theamount of mannitol in order to protect the omeprazole from contact withsolvents and with traces of water present in the binder solutionsemployed for applying the mixture of omeprazole and mannitol to theneutral grains consisting of sugar and starch. Additionally, accordingto that patent, supplementary protection of the omeprazole applied toneutral grains is obtained by means of a second protective layerconsisting of mannitol and a binder solution in order to definitivelyisolate the core onto which the omeprazole and the mannitol is applied.This supplementary protection isolates the omeprazole from the outercoating layer that is designed to ensure gastro-protection of the activecores.

WO96/01624 in the name of ASTRA discloses a tableted dosage formcomprised of individually enteric coated layered units of a corematerial comprising a benzimidazole ingredient. Said individuallyenteric coated layered units are mixed with tablet excipients andcompressed together. Said tablet excipients are e.g. microcrystallinecellulose. The resulting tablet is said to withstand acidic environment.

SUMMARY OF THE INVENTION

The applicant has studied possible novel pharmaceutical compositionsdesigned for oral administration of acid-labile substances, and notablyomeprazole, pantoprazole, lansoprazole, leminoprazole and pariprazole,which have excellent storage stability together with stability duringtheir preparation process, and has surprisingly found novel compositionsthat are particularly stable that do not include eitheralkaline-reacting compounds nor mannitol in a substantiallystoechiometric amount, which are both stated as being essential in theprior art.

Thus, the present invention provides a composition exempt ofalkaline-reacting compounds comprising:

(a) a core containing an acid-labile benzimidazole active principle,said core being constituted of nuclei and said active ingredient mixedtogether and then compressed together, and said active principle notbeing in the form of an alkaline salt;

(b) an intermediate layer; and

(c) an enteric layer.

According to one embodiment, said nuclei and said active ingredient aregranulated together and then compressed together.

According to one preferred embodiment, the nuclei have a particle size,in the absence of the active principle, comprised between 80 and 500 μm,preferably comprised between 150 and 300 μm.

According to a preferred embodiment, in the composition, pharmaceuticalexcipients, preferable at least one lubricant, are additionally presentwith said nuclei and said active ingredient.

According to another embodiment, at least one lubricant selected fromthe group comprising: sodium stearylfumarate, magnesium stearate,glyceryl behenate and talc is additionally present with said nuclei andsaid active ingredient.

According to another embodiment, the intermediate layer containssilicium dioxide.

Omeprazole, lansoprazole, pantoprazole, leminoprazole or pariprazole areexamples of acid-labile benzimidazole active principle. The inventionalso provides a method for preparing a composition according to theinvention, comprising the steps of:

(i) mixing nuclei with an active principle;

(ii) compressing the product of step (i) to form a core containing anactive principle;

(iii) coating said core with an intermediate layer; and

(iv) coating a product from step (iii) with an enteric layer.

According to an embodiment, step (i) is granulation.

According to another embodiment, said step (i) is carried out byspraying a medium containing an active principle onto nuclei in afluidized bed granulator followed by drying the product thus obtained.

The medium containing the active principle is preferably an aqueousmedium.

According to another embodiment, the instant process additionallycomprises the step of mixing nuclei or the product of step (i) withpharmaceutical excipients, preferably with at least one lubricant.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in detail with reference to theattached drawings in which:

FIG. 1 shows the stability of the composition of example 1;

FIG. 2 shows the stability of a prior art composition, Prilosec®.

FIG. 3 is a photograph of granules obtained by fluidized bed granulationaccording to the examples.

DETAILED DESCRIPTION

Here, the expression "acid-labile substance" should be taken to meansubstances the breakdown half-life of which is less than 10 minutesand/or is comprised substantially between 10 minutes and 65 hours inaqueous solutions having, respectively a pH less than 4 and/or a pH of7. Typically, the active principles disclosed in EP 244,380 can be citedas examples, and notably omeprazole, pantoprazole, lansoprazole,leminoprazole and pariprazole.

Here, the expression *benzimidazole active principle should be taken tomean benzimidazole derivatives that are of therapeutic value. Thebenzimidazole active principles disclosed in the description notablycomprise omeprazole, pantoprazole, lansoprazole, leminoprazole andpariprazole together with benzimidazole derivatives described in EP 244380, U.S. Pat. No. 4,045,563, EP-0 005 129, BE-898 880, GB-2 141 429,EP-0 146 370, GB-2 082 580, EP-A-0 173 664, EP-A-0 080 602, 30 EP-0127763, EP-0 134 400, EP-0 130 729, EP-0 150 586, DE-34 15971, GB-2 082580, SE-A-8504048-3 and U.S. Pat. No. 4,182,766. In this invention, aredescribed preferably the compounds stated as being preferred in thosedocuments and in particular omeprazole, pantoprazole, lansoprazole,leminoprazole and pariprazole; the alkaline salt form of the activeprinciples cited above being excluded. Derivatives, such as salts(hydrates, etc.), esters and the like (including pro-drugs), are alsocontemplated, inasmuch as they are not of alkaline nature.

Mixtures of active principles are also envisaged, for example thosecomprising a benzimidazole in association with another active principle,or those containing two benzimidazoles.

Here, the expression "exempt of alkaline-reacting compound" should betaken to mean a composition that substantially does not contain anyalkaline-reacting compound, in other words a composition in which theamount of alkaline-reacting compound is not sufficient to set up analkaline micro-environment around the active principle when it is incontact with an acid or neutral aqueous medium, for example amicro-environment having a pH above 7.

According to this invention the core consists of a set of nuclei basedon pharmaceutical-inert excipients with which the acid-labile activeprinciple has been mixed, i.e. purely mixed, deposited, coated,aggregated, and then having been compressed together.

The expression "nuclei and active ingredient mixed together and thencompressed together" covers various embodiments.

According to one embodiment, the process used for the manufacture of theinstant cores is granulation, preferably fluidized bed granulation. Oneskilled in the art is fully aware of that technique. Elements ofinterest regarding said process may however be found in the publicationof Schaefer & Worts, Arch. Pharm. Chemi. Sci., Ed5, 1977, 51-60.According to said granulation technique, the nuclei, e.g. lactose, arefluidized together with the inlet air, and a (binder) solution of theactive ingredient is sprayed on the fluidized bed. Granules are thenformed of nuclei and active ingredient; said granules are morespecifically shown in FIG. 3. It can be seen that the solution formes abinder that holds together several nuclei; agglomeration also occursbetween nuclei and/or between benzimidazole particles. Said granules,which can be considered as intermediates, are then compressed together.

Alternative embodiments may be used, e.g. where the active ingredient ispresent onto the nuclei, which are then compressed together, or wherethe active ingredient and/or the nuclei are (partially) subject toagglomeration, and then agglomerated nuclei and/or agglomerated activeingredient and nuclei with active ingredient onto same are compressedtogether.

Another process that may be used for the manufacture is the tank coatingtechnique, where the nuclei are introduced into a solution of the activeingredient, and the resulting slurry is compressed, optionally after apreliminary drying step.

Another way to express the technique for manufacturing the nuclei+activeingredient is to call it "coating technique", since a lot of possibleembodiments lead to products that can be qualified as coated products".Thus, in the instant description, the term "coating step" may be used inlieu of the term "mixing step".

In fact, on a macroscopic scale, the core may be considered as a corehaving dispersed therein the active ingredient.

Here, the expression "a pharmaceutically-acceptable inert excipient"should be taken to mean a compound that does not lead to a chemicalreaction under operating conditions employed that can lead to breakdownof the active principle.

The nuclei can be any substance that is pharmaceutically inert vis-a-visthe active principle and can be crystalline or amorphous. These nucleimay, in general, be composed of a sugar, such as lactose, saccharose,corn starch etc. or any one of the mixtures thereof. The activeprinciple which is optionally mixed with pharmaceutical excipients, isapplied to the nuclei using any conventional coating technique employed,for example, in a suitable coating tank or in a fluidized bed devicesuch as a granulator, with the use of suitable aqueous and/or organicsolvents, or using a dry process. Coating is preferably carried out in afluidized bed granulator. Typically Polysorbate 80 or sodium laurylsulfate mixed with the active principle are added. Preferably, alubricant, and notably sodium stearylfumarate or magnesium stearate orglyceryl behenate (Ompritol 888 ATO) or (micronized) talc are addedafter the active principle has been deposited on the inert nuclei.

Any conventional excipients used in the pharmaceutical and chemicalfield that are compatible with the active principle may be used, such asbinders, fillers, plastifiers, surfactants, pigments, disintegratingagents, lubricants, wetting agents, etc., excepting alkaline-reactingcompounds. The following can be cited as examples of excipients suitablefor use in the present invention: polysorbate 80 (Tween®80), sodiumlauryl sulfate, hydroxypropylcellulose, hydroxypropylmethylcellulose,talc, microcrystalline cellulose, colloidal silica,polyvinyl-pyrrolidone, sodium stearylfumarate, magnesium stearate,titanium dioxide, etc.

The intermediate layer, according to the invention consists of at leastone sub-layer. It corresponds to one or several inert water-solublelayers or layers which rapidly disintegrate in an aqueous medium,containing non-acid inert pharmaceutical excipients. This layercomprises at least one polymer conventionally used in applications wherea film is provided by coating such as: sugars, polyethyleneglycol,polyvinylpyrolidone, poly(vinyl alcohol), hydroxypropylcellulose,hydroxymethylcellulose, hydroxypropylmethylcellulose, etc. Theintermediate layer can additionally contain any one of the conventionalpharmaceutical excipients cited in the section relating to the core, ora mixture thereof, and notably silicon dioxide. This silicon dioxide ispresent in an amount which can vary between 2 and 45% by weight based onthe dry weight of the intermediate layer, preferably 5 to 18% by weight,for example about 9%.

This intermediate layer is applied to the core using any coatingtechnique conventionally employed in a suitable coating tank or in afluidized bed device, with the use of suitable aqueous and/or organicsolvents, or by using latex suspensions of said excipients.

The enteric layer according to this invention corresponds to a layerthat is entero-soluble and gastro-resistant. It is applied to theintermediate layer by conventional coating techniques such as coating ina tank or a fluidized bed employing polymer solutions in water or insuitable organic solvents or using latex suspensions of these polymers.As a polymer, use can be made of: cellulose acetyl phthalate,hydroxypropyl-methylcellulose phthalate, polyvinyl phthalate acetate,methacrylic acid methyl esters/methacrylic acid copolymers, such as forexample, compounds known under the Eudragit®L12.5 or Eudragit®L100 (RohmPharma) trademarks, or similar compounds conventionally employed for thepreparation of enteric coatings, as well as mixtures thereof.

The enteric coating can also be applied using aqueous dispersions ofpolymers, for example Aquateric® (FMC Corporation), Eudragit®L100-55(Rohm Pharma), CE5142 coating (BASF). The enteric layer can also containa pharmaceutically-acceptable plastifying agent such as, for example,ketanol, triacetine, citric acid esters such as those known under theCitroflex® (Pfizer) trademarks, phthalic acid esters, dibutylsuccinateor any other similar plastifying agent. The amount of plastifying agentis in general optimized for each polymer and generally represent 1 to30% of the polymer, for example from 5 to 20%. Supplementary agents suchas talc, pigments, coloring agents, flavoring agents, as well as anyother excipient that conventionally enters into the composition ofenteric coatings can be employed.

The compositions according to the present invention generally comprise acore representing 40 to 90% by weight, preferably 60-70% by weight basedon the total weight of the composition, an intermediate layerrepresenting 5 to 30% by weight, preferably 15 to 20% by weight, basedon the total weight of the composition, and an enteric layerrepresenting from 5 to 30% by weight, preferably 15-20% by weight basedon the total weight of the composition. The core generally includes theactive principle and in an amount of from 2 to 50% preferably from 5 to20% by weight.

In one preferred embodiment, the composition according to the inventionis provided in a tablet form (single, beakable, etc.).

In another prefered embodiment, the composition is in the form ofmicro-tablets enclosed inside a capsule, e.g. a gelatin capsule. Forthis, any gelatin capsule conventionally employed in the pharmaceuticalformulation field can be used, such as the hard gelatin capsule known asCapsugel, available from Eli Lilly.

The compositions of this invention are particularly suitable for oraladministration of the active principles and are particularly suitablefor treating gastro-intestinal sicknesses.

According to one particular embodiment, the composition according tothis invention takes the form of a capsule containing 16 micro-tablets,having the following composition, expressed in mg/per capsule, startingfrom the core and moving outwards: lactose 50-500, active principle10-40, hydroxypropylmethylcellulose 1-100, Polysorbate 80 or sodiumlauryl sulfate 0.0-5.0, sodium stearylfumarate or magnesium stearate0.8-8.0, crospovidone 0-50; intermediate layer: talc 0-20, titaniumdioxide 0-20, silicon dioxide 0-20, hydroxypropylmethylcellulose 3-50;enteric layer: methacrylic acid copolymer, type C 5-50, triethyl citrate0-15, talc 0-30.

The water needed to produce each component is present in an amount offrom 30 to 1000 as regards the core, 10-500 as regards of theintermediate layer and 0-1000 as regards the enteric layer. It ishowever also possible to use another medium, such as a medium containingwater and another solvent, such as alcohol.

The invention will now be described in more detail on the basis of thefollowing examples which are only provided by way of illustrativeexample.

EXAMPLE 1

Preparation of a pharmaceutical composition of omeprazole intended fororal administration.

A pharmaceutical composition according to the present invention, in theform of micro-tablets contained in a gelatin capsule having thefollowing composition, expressed in mg, was prepared.

    ______________________________________                                                        per     per capsule                                                           microtablet                                                                           (× 16 tablets.)                                 ______________________________________                                        1 - Composition of core:                                                      Omeprazole        1.250     20.00                                             Hydroxypropylmethylcellulose                                                                    0.625     10.00                                             Lactose           11.875    190.00                                            Sodium stearylfumarate                                                                          0.150     2.40                                              Crospovidone      0.750     12.00                                             Water             7.500     120.00                                            2 - Composition of intermediate layer                                         Talc              0.375     6.00                                              Titanium dioxide  0.150     2.40                                              Hydroxypropylmethylcellulose                                                                    0.750     12.00                                             Water             5.000     80.00                                             3 - Composition of the enteric layer                                          methacrylic acid copolymer,                                                                     1.375     22.00                                             type C                                                                        triethyl citrate  0.206     3.30                                              Talc              0.275     4.40                                              Water             3.750     60.00                                             ______________________________________                                    

First, the core is prepared by dissolving hydroxypropylmethylcellulosein water followed by addition of the omeprazole and homogenization ofthe resulting suspension. The omeprazole suspension thus obtained issprayed onto lactose nuclei having a particle size of 250 15 μm, in asuitable fluidized bed granulator, such as a granulator sold by thecompanies Glatt, Aeromatic, etc. Any type of fluidized bed granulatorconventionally used for this type of step can be employed with thepresent invention. After all the suspension has been sprayed, the nucleiare dried in a conventional manner, using, for example a fluidized bed,the temperature of the product preferably remaining below 45° C. Thesodium stearylfumarate and the crospovidone are than added to the driednuclei, followed by mixing. After this, compression of the mixtureobtained is carried out to obtain microtablets of a diameter of about2.5 mm (generally comprised between 2 and 4 mm); alternatively,compression of the mixture obtained is carried out to obtain tablets ofconventional dimensions. The microtablets and the tablets containsuitable amounts of the active principle.

The intermediate layer which is prepared by dissolving thehydroxypropylmethylcellulose in water followed by addition of talc andtitanium dioxide followed up by homogenization, is deposited by sprayingonto the microtablets. This operation can be carried out in any suitablecoating device that allows a regular film to be obtained, for example aGlatt coater with a Wurster type column.

The enteric layer, which is prepared by dissolving triethyl citrate in aportion of water, with addition to aqueous dispersion of methacrylicacid copolymer of type C (Eudragit L 30D-55), followed by agitation ofthe mixture obtained for 30 minutes and final addition of the talcsuspension that was prepared in parallel by homogenizing talc in theportion of water remaining, is deposited by spraying on the tabletcoated with the intermediate layer. In order to check the stability ofthe microtablets prepared according to the process described above, themicrotablets prepared were submitted to tests on their conservation at45° C. in the presence of 75% relative humidity. A prior art compositionsold under the name Prilosec®, was also tested. This prior artcomposition contains agents having an alkaline reaction. The amount ofomeprazole present in the microtablets at the end of the period ofstorage was determined by the following process: The amount ofomeprazole was determined by HPLC on a Nucleosil C18 5 μ 150×4.6 mmcolumn, using for the moving phase: buffer (8.9 g Na₂ HPO₄, 2H₂ O in1000 ml of purified water; pH adjusted to 7.6 using H₃ PO₄) in an amountof 73%/, acetonitrile in an amount of 27%. The detection consisted inmeasuring absorbency at 280 nm.

The solution of the sample to be determined was prepared as follows. Anaccurately weighed amount of the microtablets, correspondingtheoretically to about 20 mg of omeprazole was introduced into a gauged50 ml flask. After adding the moving phase, this flask was placed in anultrasound bath for 5 minutes. After the solution had returned toambient temperature, the amount in the flask was adjusted to a volume of50 ml by adding the moving phase. The concentration, Cd, in omeprazole,expressed in mg/theoretical weight of microtablets is given by thefollowing formula:

    Cd=(Aech/Aet)×(Pet/Pech)×(Vd ech/Vd et)×Pth

in which: Aech=area of peak of sample solution; Aet=area of peak ofstandard solution, this solution having been prepared under the sameconditions as the sample solution but from a determined amount ofomeprazole (20 mg); Pet =weight of the standard substance; Pech=weightof the sample; Vd ech=dilution factor of the sample; Vd et=dilutionfactor of the standard; Pth=theoretical weight of the test sample ofmicrotablets (theoretically corresponding to 20 mg of omeprazole).

The results respectively obtained after 0 days, 14 days and 30 days aregiven in FIGS. 1 and 2 respectively for the composition according to theinvention and for Prilosec®. Curves 1a and 2a represent the initialstate, the respective percentages of the areas of the omeprazole peakbeing 99.67% and 97.51% for the composition according to the inventionand, respectively, Prilosec®. Curves 1b and 2b show the situation after14 days, the percentages then being 99.56% and 75.09% respectively.Curves 1c and 2c show the state after 30 days, the percentages thenbeing 99.38% and 15.89% respectively.

EXAMPLE 2

Preparation of a pharmaceutical composition of omeprazole intended fororal administration.

A pharmaceutical composition according to the present invention in theform of microtablets contained in a gelatin capsule having the followingcomposition expressed in mg, was prepared

    ______________________________________                                                        per     per capsule                                                           microtablets                                                                          (× 16 tablets)                                  ______________________________________                                        1 - Composition of the core:                                                  Omeprazole        1.250     20.00                                             Hydroxypropylmethylcellulose                                                                    0.625     10.00                                             Lactose           11.875    190.00                                            Magnesium stearate                                                                              0.150     2.40                                              Crospovidone      0.750     12.00                                             water             7.500     120.00                                            2 - Composition of the intermediate layer                                     Talc              0.375     6.00                                              Titanium dioxide  0.150     2.40                                              Hydroxypropylmethylcellulose                                                                    0.750     12.00                                             Water             5.000     80.00                                             3 - Composition of the enteric layer                                          methacrylic acid copolymer,                                                                     1.375     22.00                                             type C                                                                        triethyl citrate  0.206     3.30                                              Talc              0.275     4.40                                              Water             3.750     60.00                                             ______________________________________                                    

The pharmaceutical composition was prepared according to the methoddescribed in example 1, except that the sodium stearylfumarate wasreplaced by magnesium stearate.

The stability of the omeprazole microtablets obtained was evaluated bythe method described in example 1. The results obtained confirm thoseobtained for the composition according to example 1, the stabilityexpressed as a percentage of omeprazole in the peak at 30 days beingbetter than 99%.

EXAMPLE 3

Preparation of a pharmaceutical composition of omeprazole intended fororal administration

A pharmaceutical composition according to the present invention in theform of microtablets contained in a gelatin capsule having the followingcomposition expressed in mg, was prepared

    ______________________________________                                                        per     per capsule                                                           microtablet                                                                           (× 17 tablets)                                  ______________________________________                                        1 - Composition of the core                                                   Omeprazole        1.176     20.0                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Lactose           6.824     116.0                                             Sodium stearylfumarate                                                                          0.103     1.75                                              Crospovidone      1.603     27.25                                             water             6.470     110.0                                             2 - Composition of the intermediate layer                                     Talc              0.294     5.00                                              Titanium dioxide  0.118     2.00                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              water             4.000     68.0                                              3 - Composition of the enteric layer                                          methacrylic acid copolymer,                                                                     1.059     18.0                                              type C                                                                        triethyl citrate  0.159     2.70                                              Talc              0.212     3.60                                              Water             4.411     75.0                                              ______________________________________                                    

The pharmaceutical composition was prepared using the method describedin example 1.

The stability of the omeprazole microtablets obtained was evaluated bythe method described in example 1. The results obtained confirm thoseobtained for the composition according to example 1.

EXAMPLE 4

Preparation of a pharmaceutical composition of omeprazole intended fororal administration

A pharmaceutical composition according to the present invention in theform of microtablets contained in a gelatin capsule having the followingcomposition expressed in mg, was prepared

    ______________________________________                                                        per     per capsule                                                           microtablet                                                                           (× 17 tablets)                                  ______________________________________                                        1 - Composition of the core:                                                  Omeprazole        1.176     20.0                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Lactose           6.824     116.0                                             sodium laurylsulfate                                                                            0.029     0.500                                             sodium stearylfumarate                                                                          0.103     1.75                                              Crospovidone      1.603     27.25                                             Water             6.470     110.0                                             2 - Composition of the intermediate layer                                     Talc              0.294     5.00                                              Titanium dioxide  0.118     2.00                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Water             4.000     68.0                                              3 - Composition of the enteric layer                                          Copolymer of methacrylic acid,                                                                  1.059     18.0                                              type C                                                                        Triethyl citrate  0.159     2.70                                              Talc              0.212     3.60                                              Water             4.411     75.0                                              ______________________________________                                    

The pharmaceutical composition was prepared using the method of example1 except that, during the preparation of the core the sodiumlaurylsulfate was dissolved in water at the same time as thehydroxymethylpropylcellulose after which the omeprazole was put insuspension in this solution.

The stability of the omeprazole microtablets obtained was evaluated bythe method described in example 1. The results obtained confirm thoseobtained for the composition of example 1.

EXAMPLE 5

Preparation of a pharmaceutical composition of omeprazole intended fororal administration

A pharmaceutical composition according to the present invention in theform of microtablets contained in a gelatin capsule having the followingcomposition expressed in mg, was prepared

    ______________________________________                                                        per     per capsule                                                           microtablet                                                                           (× 17 tablets)                                  ______________________________________                                        1 - Composition of the core:                                                  Omeprazole        1.176     20.0                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Lactose           6.824     116.0                                             Polysorbate 80    0.029     0.500                                             Sodium stearylfumarate                                                                          0.103     1.75                                              Crospovidone      1.603     27.25                                             Water             6.470     110.0                                             2 - Composition of the intermediate layer                                     Talc              0.294     5.00                                              Titanium dioxide  0.118     2.00                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Water             4.000     68.0                                              3 - Composition of the enteric layer                                          Methacrylic acid copolymer,                                                                     1.059     18.0                                              type C                                                                        Triethyl citrate  0.159     2.70                                              Talc              0.212     3.60                                              Water             4.411     75.0                                              ______________________________________                                    

The pharmaceutical composition was prepared using the method describedin example 1, except for the fact that during preparation of the core,Polysorbate 80 was dissolved in water at the same time as thehydroxyinethylpropylcellulose after which the omeprazole was put insuspension in this solution.

The stability of the omeprazole microtablets (measured as in example 1)confirmed the results obtained for the composition according to example1.

EXAMPLES 6 to 8

Preparation of pharmaceutical compositions of pantoprazole for oraladministration.

The pharmaceutical compositions according to the invention in the formof individual tablets containing 40 mg of pantoprazole active principlehaving the following composition expressed in mg/tablet were prepared.

    ______________________________________                                                        Ex.    Ex.     Ex.                                                            No. 6  No. 7   No. 8                                          ______________________________________                                        1 - Composition of the core:                                                  Pantoprazole      40.00    40.00   40.00                                      Hydroxypropylmethylcellulose                                                                    20.00    20.00   20.00                                      Lactose           120.00   120.00  120.00                                     Polysorbate 80    --        1.00   --                                         Sodium laurylsulfate                                                                            --       --      1.00                                       Sodium stearylfumarate                                                                          1.00     1.00    1.00                                       Crospovidone      20.00    20.00   20.00                                      Water             250.0    250.0   250.0                                      2 - Composition of the intermediate layer                                     Talc              2.5      2.5     2.5                                        Titanium dioxide  1.0      1.0     1.0                                        Hydroxypropylmethylcellulose                                                                    5.0      5.0     5.0                                        Water             35.0     35.0    35.0                                       3 - Composition of the enteric layer                                          Methacrylic acid copolymer,                                                                     10.00    10.00   10.00                                      type C                                                                        triethyl citrate  1.5      1.5     1.5                                        Talc              2.0      2.0     2.0                                        Water             40.0     40.0    40.0                                       ______________________________________                                    

The pharmaceutical composition was prepared using the method describedin example 1, except that firstly, during preparation of the core of thecompositions of examples 7 and 8, Polysorbate 80 and, respectively,sodium lauryl sulfate were dissolved in the water at the same time asthe hydroxymethylpropylcellulose after which the pantoprazole was putinto the suspension in the solution and, secondly, the final compositionwas obtained in the form of tablets, and not microtablets contained in acapsule.

The stability of the pantoprazole tablets obtained was evaluated by themethod described in example 1. The results obtained confirm thoseobtained for the composition according to example 1.

EXAMPLES 9-11

Preparation of pharmaceutical composition of lansoprazole for oraladministration.

Pharmaceutical compositions according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/capsule were prepared.

    ______________________________________                                                        Ex.    Ex.     Ex.                                                            No. 9  No. 10  No. 11                                         ______________________________________                                        1 - Composition of the core:                                                  lanzoprazole      30.00    30.00   30.00                                      Hydroxypropylmethylcellulose                                                                    15.00    15.00   15.00                                      Lactose           120.00   120.00  120.00                                     Polysorbate 80    --        0.75   --                                         Sodium laurylsulfate                                                                            --       --      0.75                                       Sodium stearylfumarate                                                                          1.25     1.25    1.25                                       Crospovidone      20.00    20.00   20.00                                      Water             200.0    200.0   200.0                                      2 - Composition of the intermediate layer                                     Talc              5.0      5.0     5.0                                        Titanium dioxide  2.0      2.0     2.0                                        Hydroxypropylmethylcellulose                                                                    10.0     10.0    10.0                                       Water             68.0     68.0    68.0                                       3 - Composition of the enteric layer                                          Methylacrylic acid copolymer,                                                                   28.0     10.0    10.0                                       type C                                                                        Triethyl citrate  2.7      2.7     2.7                                        Talc              3.6      3.6     3.6                                        Water             75.0     75.0    75.0                                       ______________________________________                                    

The pharmaceutical composition was prepared using the method describedin example 1, except that firstly, during preparation of the core of thecompositions of examples 10 and 11, Polysorbate 80 and, respectively,sodium lauryl sulfate were dissolved in the water at the same time asthe hydroxymethylpropylcellulose after which the pantoprazole was putinto the suspension in the solution.

The stability of the pantoprazole tablets obtained was evaluated by themethod described in example 1. The results obtained confirm thoseobtained for the composition according to example 1.

EXAMPLE 12

Preparation of pharmaceutical composition of omeprazole for oraladministration.

A pharmaceutical composition according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/was prepared

    ______________________________________                                                        per     per capsule                                                           microtablet                                                                           (× 17 tablets)                                  ______________________________________                                        1 - Composition of the core:                                                  Omeprazole        1.176     20.0                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Lactose           6.823     116.0                                             Polyplasdone XL   1.603     27.25                                             Sodium stearylfumarate                                                                          0.103     1.75                                              Water             6.471     110.0                                             2 - Composition of the intermediate layer                                     Talc (micronized) 0.176     3.00                                              Titanium dioxide  0.118     2.00                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Silicon dioxide   0.088     1.50                                              Water             5.588     95.00                                             3 - Composition of the enteric layer                                          Eudragit L 30D 55 (solid)                                                                       1.059     18.0                                              Triethyl citrate  0.159     2.70                                              Talc (micronized) 0.212     3.60                                              Water             4.412     75.0                                              ______________________________________                                    

The pharmaceutical composition was prepared using the method describedin the examples above.

The stability of the microtablets of omeprazole (measures like inexample 1) confirm the results obtained for the composition according toexample 1.

EXAMPLE 13

Preparation of a pharmaceutical composition of omeprazole for oraladministration.

A pharmaceutical composition according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/was prepared

    ______________________________________                                                        per     per capsule                                                           microtablet                                                                           (× 17 tablets)                                  ______________________________________                                        1 - Composition of the core:                                                  Omeprazole        1.176     20.0                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Lactose           6.823     116.0                                             Polyplasdone XL   1.603     27.25                                             Glyceryl behenate 0.103     1.75                                              Water             6.471     110.0                                             2 - Composition of the intermediate layer                                     Talc (micronized) 0.176     3.00                                              Titanium dioxide  0.118     2.00                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Silicon dioxide   0.088     1.50                                              Water             5.588     95.00                                             3 - Composition of the enteric layer                                          Eudragit L 30D 55 (solid)                                                                       1.059     18.0                                              Triethyl citrate  0.159     2.70                                              Talc (micronized) 0.212     3.60                                              Water             4.412     75.0                                              ______________________________________                                    

The pharmaceutical composition was prepared using the process describedfor the examples above.

The stability of the microtablets of omeprazole (measures like inexample 1) confirm the results obtained for the composition according toexample 1.

EXAMPLE 14

Preparation of pharmaceutical composition of omeprazole for oraladministration.

A pharmaceutical composition according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/was prepared

    ______________________________________                                                        per     per capsule                                                           microtablet                                                                           (× 17 tablets)                                  ______________________________________                                        1 - Composition of the core:                                                  Omeprazole        1.176     20.0                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Lactose           6.823     116.0                                             Polyplasdone XL   1.603     27.25                                             Talc (micronized) 0.103     1.75                                              Water             6.471     110.0                                             2 - Composition of the intermediate layer                                     Talc (micronized) 0.176     3.00                                              Titanium dioxide  0.118     2.00                                              Hydroxypropylmethylcellulose                                                                    0.588     10.0                                              Silicon dioxide   0.088     1.50                                              Water             5.588     95.00                                             3 - Composition of the enteric layer                                          Eudragit L 30D 55 (solid)                                                                       1.059     18.0                                              Triethyl citrate  0.159     2.70                                              Talc (micronized) 0.212     3.60                                              Water             4.412     75.0                                              ______________________________________                                    

The pharmaceutical composition was prepared using the process describedfor the examples above.

The stability of the microtablets of omeprazole (measures like inexample 1) confirm the results obtained for the composition according toexample 1.

EXAMPLES 15-17

Preparation of pharmaceutical composition of lansoprazole for oraladministration.

Pharmaceutical compositions according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/capsule were prepared.

    ______________________________________                                                        Ex.    Ex.     Ex.                                                            No. 15 No. 16  No. 17                                         ______________________________________                                        1 - Composition of the core:                                                  lanzoprazole      30.00    30.00   30.00                                      Hydroxypropylmethylcellulose                                                                    15.00    15.00   15.00                                      Lactose           120.00   120.00  120.00                                     Polysorbate 80    --        0.75   --                                         Sodium laurylsulfate                                                                            --       --      0.75                                       Glyceryl behenate 1.25     1.25    1.25                                       Crospovidone      20.00    20.00   20.00                                      Water             200.0    200.0   200.0                                      2 - Composition of the intermediate layer                                     Talc              5.0      5.0     5.0                                        Titanium dioxide  2.0      2.0     2.0                                        Hydroxypropylmethylcellulose                                                                    10.0     10.0    10.0                                       Water             68.0     68.0    68.0                                       3 - Composition of the enteric layer                                          Methacrylic acid copolymer,                                                                     18.0     10.0    10.0                                       type C                                                                        Triethyl citrate  2.7      2.7     2.7                                        Talc              3.6      3.6     3.6                                        Water             75.0     75.0    75.0                                       ______________________________________                                    

The pharmaceutical composition was prepared by the method described inexamples 9 to 11, except that, during preparation of the core, glycerylbehenate was employed instead of sodium stearyl fumarate.

The stability of the microtablets of lansoprazole (measures like inexample 1) confirm the results obtained for the composition according toexample 1.

EXAMPLE 18-20

Preparation of pharmaceutical composition of lansoprazole for oraladministration.

Pharmaceutical compositions according to the present invention, in theform of microtablets contained in a gelatin capsule, having thefollowing composition expressed in mg/capsule were prepared.

    ______________________________________                                                        Ex.    Ex.     Ex.                                                            No. 18 No. 19  No. 20                                         ______________________________________                                        1 - Composition of the core:                                                  lanzoprazole      30.00    30.00   30.00                                      Hydroxypropylmethylcellulose                                                                    15.00    15.00   15.00                                      Lactose           120.00   120.00  120.00                                     Polysorbate 80    --        0.75   --                                         Sodium laurylsulfate                                                                            --       --      0.75                                       Talc (micronized) 1.25     1.25    1.25                                       Crospovidone      20.00    20.00   20.00                                      Water             200.0    200.0   200.0                                      2 - Composition of the intermediate layer                                     Talc              5.0      5.0     5.0                                        Titanium dioxide  2.0      2.0     2.0                                        Hydroxypropylmethylcellulose                                                                    10.0     10.0    10.0                                       Water             68.0     68.0    68.0                                       3 - Composition of the enteric layer                                          Methacrylic acid copolymer,                                                                     18.0     10.0    10.0                                       type C                                                                        Triethyl citrate  2.7      2.7     2.7                                        Talc              3.6      3.6     3.6                                        Water             75.0     75.0    75.0                                       ______________________________________                                    

The pharmaceutical composition was prepared by the method described inexamples 9 to 11, except that, during preparation of the core,micronized talc was employed instead of sodium stearyl fumarate.

The stability of the microtablets of lansoprazole (measures like inexample 1) confirm the results obtained for the composition according toexample 1.

EXAMPLES 21-23

Preparation of pharmaceutical compositions of pantoprazole for oraladministration.

The pharmaceutical compositions according to the invention in the formof individual tablets containing 40 mg of pantoprazole active principlehaving the following composition expressed in mg/tablet were prepared.

    ______________________________________                                                      Ex.      Ex.     Ex.                                                          No. 21   No. 22  No. 23                                         ______________________________________                                        1 - Composition of the core:                                                  Pantoprazole    40.00      40.00   40.00                                      Hydroxypropylmethylcellulose                                                                  20.00      20.00   20.00                                      Lactose         120.00     120.00  120.00                                     Polysorbate 80  --          1.00   --                                         sodium laurylsulfate                                                                          --         --      1.00                                       Glyceryl behenate                                                                             1.00       1.00    1.00                                       Crospovidone    20.00      20.00   20.00                                      Water           250.0      250.0   250.0                                      2 - Composition of the intermediate layer                                     Talc              2.5      2.5     2.5                                        Titanium dioxide  1.0      1.0     1.0                                        Hydroxypropylmethylcellulose                                                                    5.0      5.0     5.0                                        Water             35.0     35.0    35.0                                       3 - Composition of the enteric layer                                          Methacrylic acid copolymer,                                                                     10.00    10.00   10.00                                      type C                                                                        Triethyl citrate  1.5      1.5     1.5                                        Talc              2.0      2.0     2.0                                        Water             40.0     40.0    40.0                                       ______________________________________                                    

The pharmaceutical composition was prepared by the method described inexamples 6 to 8, except that, during preparation of the core, glycerylbehenate was employed instead of sodium stearyl fumarate.

The stability of the microtablets of pantoprazole (measured like inexample 1) confirms the results obtained for the composition accordingto example 1.

EXAMPLES 24-26

Preparation of pharmaceutical compositions of pantoprazole for oraladministration.

The pharmaceutical compositions according to the invention in the formof individual tablets containing 40 mg of pantoprazole active principlehaving the following composition expressed in mg/tablet were prepared.

    ______________________________________                                                        Ex.    Ex.     Ex.                                                            No. 24 No. 25  No. 26                                         ______________________________________                                        1 - Composition of the core:                                                  Pantoprazole      40.00    40.00   40.00                                      Hydroxypropylmethylcellulose                                                                    20.00    20.00   20.00                                      Lactose           120.00   120.00  120.00                                     Polysorbate 80    --        1.00   --                                         Sodium laurylsulfate                                                                            --       --      1.00                                       Talc (micronized) 1.00     1.00    1.00                                       Crospovidone      20.00    20.00   20.00                                      Water             250.0    250.0   250.0                                      2 - Composition of the intermediate layer                                     Talc              2.5      2.5     2.5                                        Titanium dioxide  1.0      1.0     1.0                                        Hydroxypropylmethylcellulose                                                                    5.0      5.0     5.0                                        Water             35.0     35.0    35.0                                       3 - Composition of the enteric layer                                          Methacrylic acid copolymer,                                                                     10.00    10.00   10.00                                      type C                                                                        Triethyl citrate  1.5      1.5     1.5                                        Talc              2.0      2.0     2.0                                        Water             40.0     40.0    40.0                                       ______________________________________                                    

The pharmaceutical composition was prepared by the method described inexamples 6 to 8, except that, during preparation of the core, micronizedtalc was employed instead of sodium stearyl fumarate.

The stability of the microtablets of pantoprazole (measured like inexample 1) confirms the results obtained for the composition accordingto example 1.

COMPARATIVE EXAMPLE

The instant micro-tablet of example 1 are recompressed in amicrocrystalline cellulose matrix using the general procedure describedin the examples of WO96/01624. The resulting tablets show cracks ontheir surfaces, evidencing that recompression of the microtablets of theinvention according to the procedure described in the WO96/01624 patentis not successful in producing suitable tablets.

Further, said final tablets have been tested as to their dissolution ina 0.1N HCl solution, according to the general procedure described inWO96/01624. Results show that after 2 hours, the dissolution is about55%, evidencing that said final tablets cannot withstand acidicconditions.

It is clear that the particular pharmaceutical excipients described inthe compositions of examples 1 to 26 can be replaced by otherpharmaceutical excipients having the same function and which areconventionally employed in the pharmaceutical formulation field,provided that they are chemically compatible with the active principle.

All such alternative embodiments are covered by the scope of theinvention to the extent where the stability of the resultingpharmaceutical composition is not substantially affected.

The teaching of the invention extends in fact to any of the acid-labileactive principles mentioned in the introductory part of thisspecification, and notably those of the preferred embodiments and fromthe examples from the prior art. The mixing (e.g. coating, pure mixingor granulating) step of the process according to the invention can becarried out using any known technique conventionally used for thispurpose. Examples which can be mentioned are coating by immersion, drycoating, dry mixing, spray coating, spray mixing, etc.

Finally, it should be noted that additional layers or sub-layers can beadded, for the purposes of adding flavor and/or color, and/or improvingacceptability of the medicament and/or allowing it to be marked.

What is claimed is:
 1. A composition substantially free ofalkaline-reacting compounds comprising:(a) a core containing anacid-labile benzimidazole active principle, wherein said core comprisesa plurality of nuclei and said active principle mixed together and thencompressed together, and wherein said active principle is not in theform of an alkaline salt; (b) an intermediate layer surrounding thecore; and (c) an enteric layer surrounding the intermediate layer; withthe proviso that omeprazole is not the benzimidazole active principle.2. The composition according to claim 1, in which said nuclei and saidactive principle are granulated together and then compressed together.3. The composition according to claim 1, in which said nuclei have aparticle size, in the absence of the active principle, of from 80 μm to500 μm.
 4. The composition according to claim 3, in which said nucleihave a particle size, in the absence of the active principle, of from150 μm to 300 μm.
 5. The composition according to claim 1, which furthercomprises at least one pharmaceutical excipient present with said nucleiand said active principle.
 6. The composition according to claim 1, inwhich at least one lubricant selected from the group consisting ofsodium stearylfumarate, magnesium stearate, glyceryl behenate and talcis additionally present with said nuclei and said active principle. 7.The composition according to claim 1, in which the intermediate layercontains silicon dioxide.
 8. The composition according to claim 1, inwhich the acid-labile benzimidazole active principle is selected fromthe group consisting of pantoprazole, lansoprazole, leminoprazole andpariprazole.
 9. The composition according to claim 1, in which theacid-labile benzimidazole active principle is pantoprazole.
 10. Thecomposition according to claim 1, provided in a tablet form.
 11. Thecomposition according to claim 1, provided in the form of a plurality ofmicro-tablets enclosed inside a capsule.
 12. A process for preparing acomposition according to claim 1, comprising the steps of:(i) mixing aplurality of nuclei with an active principle; (ii) compressing theproduct of step (i) to form a core comprising the active principle;(iii) coating said core with an intermediate layer; and (iv) coating theproduct from step (iii) with an enteric layer.
 13. The process accordingto claim 12, in which step (i) is granulation.
 14. The process accordingto claim 12, in which step (i) is carried out by spraying a mediumcontaining an active principle onto a plurality of nuclei in a fluidizedbed granulator followed by drying the product thus obtained.
 15. Theprocess according to claim 14, in which the medium containing the activeprinciple is an aqueous medium.
 16. The process according to claim 12,additionally comprising the step of mixing nuclei or the product of step(i) with at least one pharmaceutical excipient.
 17. The compositionaccording to claim 2, in which said nuclei have a particle size, in theabsence of the active principle, of from 80 μm to 500 μm.
 18. Thecomposition according to claim 5, wherein the pharmaceutical excipientis a lubricant.
 19. The process according to claim 13, in which step (i)is carried out by spraying a medium containing an active principle ontoa plurality of nuclei in a fluidized bed granulator followed by dryingthe product thus obtained.
 20. The process according to claim 16,wherein the pharmaceutical excipient is a lubricant.